BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer

Abstract

Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.

Two Receptors, Two Isoforms, Two Cancers: Comprehensive Analysis of KIT and TrkA Expression in Neuroblastoma and Acute Myeloid Leukemia

“…In the KIT -low group we marked BAG3, SH3BP5 , and MARCKS genes as their high expression is associated with a poor prognosis (Figure 5D). BAG3 (BCL2-associated athanogene 3) knockdown is known to affect proliferation, migration, and invasion of EGFR-positive triple-negative breast cancer cell lines via AKT and FAK kinases (47). MARCKS (Myristoylated alanine-rich C kinase substrate) is involved in the tumorigenesis of different types of malignant diseases, but its role in myeloid malignances has not been described.…”

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…However, recent advances have resulted in approval of PPIis for marketing [ 550 ]. Disrupting the BAG3-HSP70 interaction has been demonstrated to sensitize TNBC cells to EGFRis [ 419 ]. BCL2-associated athanogene 3 (BAG3) is a co-chaperone for heat shock protein 70 (HSP70) and heat shock cognate 71 kDa (HSC70) chaperone proteins [ 551 , 552 ].…”

At the Crossroads of Apoptosis and Autophagy: Multiple Roles of the Co-Chaperone BAG3 in Stress and Therapy Resistance of Cancer

“…In line with these findings, Shields et al reported that BAG3 is highly expressed in a subset of TNBC cell lines and primary tumor samples, while high expression of BAG3 in TNBC patients was associated with reduced recurrence-free survival, supporting the impact of BAG3 as an adverse prognostic factor [34]. The authors also observed a positive correlation between BAG3 and EGFR expression in TNBC cells and a direct interaction between BAG3 and EGFR signaling network components using a mass spectrometry approach.…”

“…The authors also observed a positive correlation between BAG3 and EGFR expression in TNBC cells and a direct interaction between BAG3 and EGFR signaling network components using a mass spectrometry approach. In TNBC cells, the combined targeting of BAG3 and EGFR was superior to inhibition of EGFR with Cetuximab alone, again highlighting the potential of BAG3 as a therapeutic target in TNBC [34].…”